The present invention relates to a novel method for the preparation of a xcex2-lactam compound. More particularly, the present invention relates to an efficient method for the preparation of a xcex2-lactam compound having usefulness as an intermediate of xcex2-aminoacid derivatives and certain antibiotics having a chemical structure resembling that of penicillin.
As is known, xcex2-lactam ring forms the principal skeletal structure of a large number of antibiotics including penicillin as a typical example to play a core role in the physiological activity thereof. Accordingly, various synthetic methods have been reported for the preparation of a great number of xcex2-lactam compounds while most of these prior art methods have a disadvantage that synthetic procedure involves complicated steps due to the high reactivity of the xcex2-lactam ring so that it is eagerly desired to develop a simple and efficient method for the synthetic preparation of xcex2-lactam compounds.
On the other hand, it is also known that various xcex2-amino acids can be obtained from xcex2-lactam compounds by the reaction thereof with alcohols and other reagents by virtue of the high chemical reactivity of the xcex2-lactam ring.
Known methods for the synthetic preparation of a xcex2-lactam compound include a method in which an isocyanate compound and an alkene compound are reacted. See, for example, xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d, ed. by A. R. Katritzlky, et al., Pergamon Press, Oxford (1984), pages 237-362 and xe2x80x9cHigh Pressure Chemical Synthesisxe2x80x9d, ed. by J. Jurczak, et al., Elsevier (1989), pages 255-293. Although this method is advantageous because the reaction proceeds in one step to form the xcex2-lactam ring, the method has a disadvantage relative to the applicability thereof when a variety of xcex2-lactam compounds are desired because the reactivity between the reactants can be high enough only when the isocyanate compound as one of the reactants has a strongly electron-attractive group as in chlorosulfonyl isocyanate and the like or when an isocyanate compound is combined with a specific alkene compound such as allene, 2,3-dihydrofuran and the like.
With an object to provide a simple and efficient method for the synthetic preparation of a xcex2-lactam compound capable of overcoming the above described disadvantages in the prior art methods, the inventors have continued extensive investigations and previously discovered that a specific xcex2-lactam compound can be prepared by the reaction of 2,3-dihydrofuran and an isocyanate compound under specific conditions but the versatility of the method is still not good enough.
The present invention accordingly has an object to provide a novel method with high efficiency and versatility for the synthetic preparation of various kinds of xcex2-lactam compounds to be freed from the above described disadvantages and limitations in the prior art methods.
Thus, the method of the present invention for the preparation of a xcex2-lactam compound represented by the general formula 
in which R1 and R2 are, each independently from the other, a monovalent hydrocarbon group, comprises the steps of: (a) mixing an isocyanate compound represented by the general formula
R1NCO,xe2x80x83xe2x80x83(II)
in which R1 has the same meaning as defined above, and a vinyl ether compound represented by the general formula
CH2xe2x95x90CHxe2x80x94Oxe2x80x94R2,xe2x80x83xe2x80x83(III)
in which R2 has the same meaning as defined above, to form a reaction mixture; and (b) bringing the reaction mixture under a superatmospheric pressure of at least 2000 atmospheres.
Although the reaction between the isocyanate compound and the vinyl ether compound under a high pressure can proceed even at room temperature, it is preferable that the reaction mixture is heated at an elevated temperature of up to 200xc2x0 C. or, preferably, up to 130xc2x0 C. when acceleration of the reaction is desired.
As is described above, the procedure of the inventive method for the preparation of a xcex2-lactam compound is very simple and efficient because the synthetic reaction can proceed only by bringing a reaction mixture of the starting reactants under a superatmospheric pressure to give the desired compound in a high yield.
One of the starting reactants is an isocyanate compound represented by the above given general formula (II). In this general formula, R1 is a monovalent hydrocarbon group exemplified by straight-chain or branched alkyl groups having 1 to 20 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl and eicosyl groups, cycloalkyl groups having 3 to 20 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, methyl cyclohexyl and decahydronaphthyl groups, aryl groups having 6 to 20 carbon atoms such as phenyl, tolyl, xylyl, naphthyl and anthracyl groups as well as substituted aryl groups having substituent groups including halogen atoms, e.g., chlorine, bromine and fluorine atoms, alkyl groups, e.g., methyl, ethyl, propyl and butyl groups, and alkoxy groups, e.g., methoxy, ethoxy, propoxy and butoxy groups, such as chlorophenyl, bromophenyl, fluorophenyl and ethylphenyl groups, and aralkyl groups having 7 to 20 carbon atoms such as benzyl and 2-phenylethyl groups as well as substituted aralkyl groups having substituents which can be the same ones as in the above mentioned substituted aryl groups, such as methyl benzyl group.
Particular examples of the isocyanate compound represented by the general formula (II) and suitable as the starting reactant in the inventive method include: alkyl isocyanates such as methyl isocyanate, ethyl isocyanate, propyl isocyanate, butyl isocyanate, pentyl isocyanate and hexyl isocyanate; cycloalkyl isocyanates such as cyclopentyl isocyanate and cyclohexyl isocyanate; and unsubstituted and substituted aryl isocyanates such as phenyl isocyanate, naphthyl isocyanate, chlorophenyl isocyanate, bromophenyl isocyanate, fluorophenyl isocyanate, tolyl isocyanate, xylyl isocyanate and ethylphenyl isocyanate; and aralkyl isocyanates such as benzyl isocyanate and phenylethyl isocyanate.
The other of the starting reactants to be reacted with the above described isocyanate compound is a vinyl ether compound represented by the general formula (III), in which R2 is a monovalent hydrocarbon group including: straight-chain or branched alkyl groups having 1 to 20 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl and eicosyl groups; and cycloalkyl groups having 3 to 20 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, methyl cyclohexyl and decahydronaphthyl groups.
Particular examples of the vinyl ether compound represented by the general formula (III) and suitable as the starting reactant in the reaction of the inventive method include: alkyl vinyl ethers such as methyl vinyl ether, ethyl vinyl ether, propyl vinyl ether, butyl vinyl ether, pentyl vinyl ether, hexyl vinyl ether, 2-ethylhexyl vinyl ether and decyl vinyl ether; and cycloalkyl vinyl ethers such as cyclopentyl vinyl ether and cyclohexyl vinyl ether.
The reaction of the isocyanate compound of the general formula (II) and the vinyl ether compound of the general formula (III) proceeds in a molar ratio of 1:1 of these reactants but it is usually preferable that the vinyl ether compound is used in a large excess over the isocyanate compound so that the excess amount of the vinyl ether compound serves as a diluent of the reaction mixture although it is optional that the vinyl ether compound is used in an amount of 0.8 to 1.2 moles per mole of the isocyanate compound and the reaction mixture is diluted with a conventional inert organic solvent, which should preferably have relatively low polarity, such as hydrocarbon solvents, e.g., benzene, toluene, xylene and the like.
The reaction between the isocyanate compound and the vinyl ether compound proceeds by bringing the reaction mixture under a superatmospheric pressure which should preferably be as high as possible. The pressure should desirably be at least 2000 atmospheres or, preferably, in the range from 2000 to 12000 atmospheres. The reaction temperature is not particularly limitative and the reaction can proceed even at room temperature although the reaction can be accelerated by increasing the temperature while an excessively high temperature is disadvantageous due to increase in the side reactions. In consideration of the balance between the reaction velocity and side reactions, the reaction temperature should be in the range from 20 to 130xc2x0 C. The reaction time naturally depends on various factors such as the kinds of the reactants, pressure, reaction temperature and the like but the reaction is usually complete within 1 to 50 hours. In this way, the desired xcex2-lactam compound can be obtained in a high yield of, for example, 90% or even higher of the theoretical value though dependent on various conditions.